Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 2003"

Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial.

Abstract: This trial assessed the rate of virological failure at 48 weeks in adult human immunodeficiency virus (HIV) type 1-infected patients assigned indinavir/ritonavir (Idv/Rtv; 800/100 mg 2 times daily) or saquinavir/ritonavir (Sqv/Rtv; 1000/100 mg 2 times daily) in an open-label, randomized (1:1), multicenter, phase 4 design. Three hundred six patients began the assigned treatment. At 48 weeks, virological failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the Idv/Rtv and Sqv/Rtv arms, respectively. The time to virological failure did not differ between study arms (P=.76). When switching from randomized treatment was counted as failure, this was seen in 78 of 158 patients in the Idv/Rtv arm, versus 51 of 148 patients in the Sqv/Rtv arm (P=.009). A switch from the randomized treatment occurred in 64 (41%) of 158 patients in the Idv/Rtv arm, versus 40 (27%) of 148 patients in the Sqv/Rtv arm (P=.013). Sixty-four percent of the switches occurred because of adverse events. A greater number of treatment-limiting adverse events were observed in the Idv/Rtv arm, relative to the Sqv/Rtv arm. In conclusion, Rtv-boosed Sqv and Idv were found to have comparable antiretroviral effects in the doses studied.

Molecular analysis of astrocytomas presenting after age 10 in individuals with NF1.

Abstract: Background: Fifteen to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade astrocytomas. Although brain tumors are less common in teenagers and adults with NF1, recent studies have suggested that patients with NF1 are at a significantly increased risk of developing astrocytomas. Objectives: To investigate the genetic basis for astrocytoma development in patients with NF1 beyond the first decade of life. Methods: The authors performed molecular genetic analyses of 10 NF1-associated astrocytomas representing all World Health Organization (WHO) malignancy grades using fluorescence in situ hybridization, loss of heterozygosity, immunohistochemistry, and direct sequencing. Results: Later-onset NF1-associated astrocytomas, unlike histologically identical sporadic astrocytomas, exhibit NF1 inactivation, supporting a direct association with NF1 rather than a chance occurrence. Furthermore, some of these astrocytomas have homozygous NF1 deletion. In addition, genetic changes observed in high-grade sporadic astrocytomas, including TP53 mutation and CDKN2A/p16 deletion, are also seen in NF1-associated high-grade astrocytomas. Conclusions: Neurofibromatosis type 1–associated astrocytomas occurring in patients older than 10 years exhibit genetic changes observed in sporadic high-grade astrocytomas. Patients with neurofibromatosis type 1 and germline NF1 deletions may be at risk for developing late-onset astrocytomas.

Myocardial contrast echocardiography is superior to other known modalities for assessing myocardial reperfusion after acute myocardial infarction

Abstract: Background: Angiographic flow measurements do not define perfusion accurately at a microvascular level, so other techniques which assess flow at a tissue level are to be preferred. Objectives: To compare intravenous myocardial contrast echocardiography (MCE) with other methods of assessing microvascular reperfusion for their ability to predict left ventricular function at one month after acute myocardial infarction. Design: 15 patients underwent primary percutaneous coronary angioplasty for acute myocardial infarction, with restoration of TIMI grade 3 flow. Corrected TIMI frame count (cTFC), myocardial blush grade (MBG), and percentage ST segment resolution at 90 and 180 minutes were recorded. Baseline regional wall motion score index (WMSI) and regional contrast score index (RCSI) were obtained 12–24 hours after the procedure, with a final regional WMSI assessment at one month. Results: Mean (SD) cTFC was 27 (9.4), and ST segment resolution was 69 (22)% at 90 minutes and 77 (20)% at 180 minutes. MBG values were 0 in six patients, 2 in two, and 3 in seven. Baseline regional WMSI, RCSI, and follow up WMSI were 2.7 (0.71), 1.5 (0.71), and 1.6 (0.73), respectively. The correlation coefficient between RCSI and follow up WMSI was 0.82 (p = 0.0012). Peak CK correlated with follow up WMSI (R = 0.80). None of the other reperfusion assessment techniques correlated significantly with follow up WMSI. Multiple regression analysis showed that a perfused hypokinetic or akinetic segment was 50 times more likely to recover function than a non-perfused segment. MCE predicted segmental myocardial recovery with a sensitivity of 88%, a specificity of 74%, and positive and negative predictive values of 83% and 81%, respectively. Conclusions: MCE is currently the best and most accurate measure of reperfusion at a microvascular level and an excellent predictor of left ventricular function at one month following acute myocardial infarction.

Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations.

Abstract: DCX mutations cause mental retardation in male subjects with lissencephalypachygyria and in female subjects with subcortical band heterotopia (SBH). We observed four families in which carrier women had normal brain magnetic resonance imaging (MRI) and mild mental retardation, with or without epilepsy. Affected male subjects had SBH or pachygyria-SBH. In two families, the phenotype was mild in both genders. In the first family, we found a tyr138his mutation that is predicted to result in abnormal folding in the small hinge region. In the second family, we found an arg178cys mutation at the initial portion of R2, in the putative β-sheet structure. Carrier female subjects with normal MRI showed no somatic mosaicism or altered X-inactivation in lymphocytes, suggesting a correlation between mild mutations and phenotypes. In the two other families, with severely affected boys, we found arg76ser and arg56gly mutations within the R1 region that are predicted to affect DCX folding, severely modifying its activity. Both carrier mothers showed skewed X-inactivation, possibly explaining their mild phenotypes. Missense DCX mutations may manifest as non-syndromic mental retardation with cryptogenic epilepsy in female subjects and SBH in boys. Mutation analysis in mothers of affected children is mandatory, even when brain MRI is normal. Ann Neurol 2003

Venous thromboembolism in the antiphospholipid syndrome: management guidelines for secondary prophylaxis

Abstract: Venous thromboembolism (VTE) in patients suffering from the antiphospholipid syndrome (APS) has been reported in almost any location of the vessel tree and the risk of recurrences has been found in several studies to be more closely associated with the presence of lupus anticoagulant than with the positivity for anti-cardiolipin antibodies. The thrombophilic state of APS raises the problem of the secondary prophylaxis to avoid VTE recurrences. For APS patients with VTE, published data appear to support a longer warfarin treatment if compared with the standard management of antiphospholipid (aPL)-negative patients with VTE. The question of how long oral anticoagulant treatment should be continued for APS patients, however, remains unanswered. Concerning the intensity of anticoagulation, several authors recommend a target international normalized ratio (INR) between 3.0 and 4.0 to efficiently protect from VTE recurrences. A recent decision analysis study does support such a suggestion. On the contrary, in a few prospective studies regimens with lower target INRs appear to be effective, and some authors therefore recommend a target INR of between 2.0 and 3.0. Specific large and prospective trials are needed to address this question. Until such information becomes available, individualized treatment according to the patient's individual risk factors for both bleeding and thrombosis is the general practice.

Anticholinergic therapy for chronic asthma in children over two years of age

Abstract: BACKGROUND In the intrinsic system of controlling airway calibre, the cholinergic (muscarinic) sympathetic nervous system has an important role. Anticholinergic, anti muscarinic bronchodilators such as ipratropium bromide are frequently used in the management of childhood airway disease. In asthma, ipratropium is a less potent bronchodilator than beta-2 adrenergic agents but it is known to be a useful adjunct to other therapies, particularly in status asthmaticus. What remains unclear is the role of anticholinergic drugs in the maintenance treatment of chronic asthma. OBJECTIVES To determine the effectiveness of anticholinergic drugs in chronic asthma in children over the age of 2 years. SEARCH STRATEGY The Cochrane Airways Group trials register and reference lists of articles were searched in January 2002. SELECTION CRITERIA Randomised controlled trials in which anticholinergic drugs were given for chronic asthma in children over 2 years of age were included. Studies including comparison of: anticholinergics with placebo, and anticholinergics with any other drug were included. DATA COLLECTION AND ANALYSIS Eligibility for inclusion and quality of trials were assessed independently by two reviewers. MAIN RESULTS Eight studies met the inclusion criteria.Three papers compared the effects of anticholinergic drugs with placebo, and a meta-analysis of these results demonstrated no statistically significant benefit of the use of anticholinergic drugs over placebo in any of the outcome measures used. The results of one of these trials could not be included in the meta-analysis but the authors did report significantly lower symptom scores with inhaled anticholinergics compared with placebo. However, there was no significant difference between ipratropium bromide and placebo in the percentage of symptom-free nights or days. Two trials studied the effects of anticholinergics on bronchial hyper responsiveness to histamine, by measuring the provocation dose of histamine needed to cause a fall of 20 % in FEV1 (PD 20). One study (comparing anticholinergics with placebo) reported a statistically significant increase in PD 20 but this was not found in another study (comparing anticholinergics with a beta-2 agonist). Both trials also examined the effect of anticholinergic drugs on diurnal variation in peak expiratory flow rate (PEFR) and reported no significant effect. Two studies compared the addition of an anticholinergic drug to a beta-2 agonist with the beta-2 agonist alone. Both trials failed to show any significant benefit from the long term use of combined anticholinergics with beta-2 agonists compared with beta-2 agonists alone. One trial compared the effects of oral and inhaled anticholinergic drugs with placebo. No statistically significant differences were found in any of the outcome measures except for a higher FEV1 / VC ratio and RV / TLC ratio with oral anticholinergic therapy when compared with placebo. REVIEWER'S CONCLUSIONS The present review summarises the best evidence available to date. Although there were some small beneficial findings in favour of anticholinergic therapy, there is insufficient data to support the use of anticholinergic drugs in the maintenance treatment of chronic asthma in children.

Characterizing one of the DQ2 candidate epitopes in coeliac disease: A-gliadin 51-70 toxicity assessed using an organ culture system.

Abstract: ObjectiveTo investigate, using an organ culture system, in-vitro toxicity of region 51–70 of A-gliadin (SQQPYLQLQPFPQPQLPYSQ), a peptide overlapping some of the sequences recently characterized as DQ2-restricted T-cell epitopes in coeliac disease.MethodsJejunal biopsies obtained from each of ten coe

Open surgery for thoracic aortic disease

Abstract: While new technologies appear to offer potential advantages over traditional therapies for thoracic aortic disease, open surgery is still the mainstay of treatment for the overwhelming majority of patients Many recent technical advances have enhanced the safety of open surgery of the descending thoracic aorta. Previous to the refinement of these adjuncts and techniques, surgeons such as Stanley Crawford showed that simple aortic cross-clamping with expeditious surgery produced the best results.1 In Crawford’s era of “clamp and go”, time limitations pressured surgeons to perform anastomoses rapidly with perfect haemostasis. The duration of aortic cross-clamping was directly related to survival and to serious complications such as paraplegia and visceral ischaemia. The role of bypass, intercostal reimplantation, and cerebrospinal fluid drainage was unclear, in that none of these techniques appeared to be beneficial. Cross-clamping the aorta below the left common carotid artery and above the coeliac axis increases proximal systemic pressure, which in turn increases the cerebrospinal fluid pressure. In addition, the mean arterial pressure distal to the clamp will fall, and therefore the distal spinal cord will be at risk of ischaemia from a combination of decreased arterial perfusion and increased cerebrospinal fluid pressure. Logically, techniques that help to reduce the cerebrospinal fluid pressure and increase the distal arterial pressure will help to treat these two adverse factors, and will consequently lower the incidence of paraplegia. Cerebrospinal fluid drainage prevents elevation of the cerebrospinal fluid pressure, and several techniques can increase the distal arterial perfusion pressure, such as a simple shunt, partial heart bypass (from the left atrium or the pulmonary veins to the left …